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The Many Faces of Personalized Health Care: Pediatric and Medical Oncology

The Many Faces of Personalized Health Care: Pediatric and Medical Oncology. Joshua D. Schiffman, MD Edward B. Clark, MD Chair in Pediatric Research Associate Professor, Pediatric Hematology/Oncology University of Utah School of Medicine. April 01, 2014. The Cancer Challenge.

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The Many Faces of Personalized Health Care: Pediatric and Medical Oncology

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  1. The Many Faces of Personalized Health Care: Pediatric and Medical Oncology Joshua D. Schiffman, MD Edward B. Clark, MD Chair in Pediatric Research Associate Professor, Pediatric Hematology/Oncology University of Utah School of Medicine April 01, 2014

  2. The Cancer Challenge • Second leading cause of death worldwide • 8 million deaths per year worldwide • 15 people die from cancer every minute • 1/2 of all men and 1/3 of all women will get cancer • Relapse is leading cause of cancer-related death

  3. Translational Oncology Core Pilot Study Huntsman Cancer Institute ARUP Laboratories

  4. Translational Oncology Core Pilot Study • Enroll RELAPSED cancer patients (N=200) • Pre- and post-test survey to clinician • Sequenom Panel (OncoCarta Custom) • 277 mutation in 25 genes • Return report to clinician • OncoScan Array V3.0 (N=48) • Genome-wide Copy Number/LOH • 74 Mutations in 9 Genes

  5. Translational Oncology Core Pilot Study • Sequenom: • ABL1, AKT1, AKT2, BRAF, CDK4, CTNNB1, EGFR, ERBB2, FGFR1, FGFR3, FLT3, HRAS, JAK2, JAK3, KIT, KRAS, MET, MYC, NRAS, PDGFRA, PIK3CA, PTEN, RB1, RET, VHL • OncoScan (Affy): • BRAF, KRAS, EGFR, IDH1, IDH2, PTEN, PIK3CA, NRAS, TP53

  6. …So what did we find?

  7. Huntsman Cancer Institute: Molecular Diagnostic/Translational Oncology Core (TOC) Pilot Study • Positive Mutation Frequency 48 out of 137 specimens were positive for ≥1 mutation (35%)

  8. Huntsman Cancer Institute: Molecular Diagnostic/Translational Oncology Core (TOC) Pilot Study Tumor Types Analyzed by OncoScan (N=48) 15 ovarian/endometrial 15 colorectal tumors 12 melanoma 4 lung tumor 1 brain tumor 1 thyroid tumor

  9. Clinically actionable/relevant copy number genes (N=100) ABL1, AKT1, AKT2, ALK, APC, AR, ARID1A, ASXL1, ATM, AURKA, BAP, BAP1, BCL2L11, BCR, BRAF, BRCA1, BRCA2, CCND1, CCND2, CCND3, CCNE1, CDH1, CDK4, CDK6, CDK8, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CEBPA, CTNNB1, DDR2, DNMT3A, E2F3, EGFR, EML4, EPHB2, ERBB2, ERBB3, ESR1, EWSR1, FBXW7, FGF4, FGFR1, FGFR2, FGFR3, FLT3, FRS2, HIF1A, HRAS, IDH1, IDH2, IGF1R, JAK2, KDM6A, KDR, KIF5B, KIT, KRAS, LRP1B, MAP2K1, MAP2k4, MCL1, MDM2, MDM4, MET, MGMT, MLL, MPL, MSH6, MTOR, MYC, NF1, NF2, NKX2-1, NOTCH1, NPM, NRAS, PDGFRA, PIK3CA, PIK3R1, PML, PTEN, PTPRD, RARA, RB1, RET, RICTOR, ROS1, RPTOR, RUNX1, SMAD4, SMARCA4, SOX2, STK11, TET2, TP53, TSC1, TSC2, VHL Ciriello et al., Nat Genet. (2013) / Frampton et al., Nat Biotechnol. (2013) Pritchard et al., J MolDiagn. (2014) / Andre et al., Lancet Oncol. (2014)

  10. TOC Colorectal Adenocarcinoma OncoScan Results (N=15) Genome view (Nexus, BioDiscovery, Inc.)

  11. Copy number aberrations in 15 colorectal adenocarcinoma cases

  12. Metastatic tumor (left ovary) 90% tumor content by Sequenom KRAS G12S mutation BMP-039

  13. Metastatic tumor (left ovary) 90% tumor content by Sequenom KRAS G12S mutation BMP-039

  14. Focal CCND1 gain (4 copies) in LOH region in case BMP-18 Metastatic CRC (liver and bile duct) 50% tumor content by Sequenom KRAS G12D mutation

  15. Focal CDK6 gain (7 copies) in BMP-46 Metastatic CRC (right colon) 30% tumor content by Sequenom KRAS G12C mutation

  16. Next Study Design: 360 Degree Profiling Mutation Panel Genome-wide copy number Genome-wide transcriptome Genome-wide methylation • Relapsed Pediatric Tumors • Relapsed Colorectal Cancer • Relapsed Ovarian/Endometrial • Relapsed Melanoma • Relapsed Sarcoma

  17. Utah and Pediatric Cancer

  18. Tumors found by early screening (Utah) Grade III AA Lung Adenoca. Grade II Glioma 17 yo girl (TP53) 41 yo woman (TP53) 24 yo man (TP53) 9 yo boy (TP53) Renal Cell Carcinoma Carotid Body Tumor Carotid Body Tumor Pheochromocytoma 30 yo man (SDHB) 58 yo man (SDHB) 34 yo man (SDHB) 51 yo woman (SDHB)

  19. Screening TP53 mutation carriers 100% Survival! 8 LFS families • 33 TP53mut + • 18 surveillance • 12 no surveillance Surveillance • 10 tumors, 7 pts • All pts alive No Surveillance • 12 tumors, 10 pts • 2 alive (20%) 20% Survival P=0.0056 Villani et al. Lancet Oncology (2011)

  20. Cancer Genetics Study (CGS) • Familial cancer syndrome global registry and biospecimen bank • Enroll children and families at high risk for cancer • DNA, cell lines, and tumor samples • Biology and clinical data linked to family pedigrees • Participants linked to UPDB Bella Johnson, Anne Naumer, Wendy Kohlmann

  21. Cancer Genetics Study • Data collection • Cancer history • Medical history • Genetic testing • Cancer screening • Patient reported family history • Linked to UPDB genealogy records • Databases • CCR, Subject, itBioPath, Progeny

  22. Cancer Genetics Study • Sample collection • 1ACD tube for cell lines (limited availability) • 1 EDTA tube for DNA and plasma • 1 Red top tube for serum • 1 PAXgene tube for RNA • 1 CPT tube for PBMC • Archived tissue or excess tissue from surgery if not already in TRAC

  23. PCH Pediatric Cancer Program • Life Course Health Care Complications and Costs – Anne Kirchhoff, PhD • Value-Based Pediatric Clinical Cancer Care – Richard Lemons, MD PhD • Advanced Therapeutic Approaches to Pediatric Cancer – Mike Spigarelli, MD PhD • Identifying New Genes and Novel Screening Approaches for Pediatric Cancer – Joshua Schiffman, MD

  24. “I’m not sure that you guys are really going to be able to find anything with this study if you are stupid enough to drive out here in this weather.” DICER1 Family

  25. Summary • Precision Oncology is happening now at University of Utah • Early tumor surveillance in patients at genetic risk for cancer saves lives • PCH Pediatric Cancer Program identifying late effects, toxicities, pharmaco-dynamics, and genetic risks • UGP is finding cancer-associated genes

  26. Questions? Joshua.Schiffman@hci.utah.edu

  27. Schiffman Lab Lisa Abegglen Christin Christensen Ashley Chan Marcus Stucki Jamie Gardiner Tonya Santoro Kristy Lee Sharanya Raghunath Clint Mason ARUP Sarah South, Xinjie Xu, Erica Andersen, Reha Toydemir Nexus (BioDiscovery) Soheil Shams, PhD RESEARCH SUPPORT: ASH Scholar Fellowship Award Curesearch Foundation (Children’s Oncology Group) St. Baldrick’s Foundation Alex’s Lemonade Stand Foundation SARC Career Development Award Children’s Health Research Career Development Award (5K12HD001410-09) Damon Runyon Clinical Investigator Award Leukemia & Lymphoma Society 1R01CA161780-01 (NCI/NIH)

  28. Colorectal Cancer Mutation Summary 14/15 (93%) = Copy Number Present 8/15 (53%) = KRAS mutations 2/15 (13%) = PIK3CA mutations 2/15 (13%) = BRAF mutations 1/15 (7%) = JAK3 mutation

  29. Ovarian and Endometrial Samples (N=15): Mutation Summary 14/15 (93%) = Copy Number Present 4/15 (27%) = PIK3CA mutations 2/15 (13%) = PTEN mutations 2/15 (13%) = TP53 mutations

  30. Metastatic Melanoma (N=12):Mutation Summary 12/12 (100%) = Copy Number Present 4/12 (33%) = NRAS mutations 2/12 (17%) = BRAF mutations 1/12 (8%) = PTEN mutation 1/12 (8%) = PIK3CA mutation

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